The widespread and common use of antibiotics to treat many infectious diseases has allowed for the selection and continual emergence of multiple-drug resistant pathogens. There is an urgent need for the development of novel antibiotics to target these infections. This research project will focus on finding novel therapies to treat methicillin-resistant Staphylococcus aureus (MRSA). Previous work by William Fenical and Paul Jensen at Scripps Institution of Oceanography showed deep ocean sediments contain actinomycetes that produce a rich and diverse array of natural products. Two new classes of compounds with novel structures, the marinopyrroles and napyradiomycins, have been identified from marine actinomycete bacteria. These compounds exhibit promising preliminary data, showing potent antibiotic activities against drug-resistant MRSA. The overall goal of this project is evaluate the pharmacological and therapeutic potential of these two novel classes of antibiotics in treating infections caused by drug-resistant MRSA. We will investigate and evaluate the marinopyrrole and napyradiomycin classes of compounds as detailed in three specific aims, creating interdisciplinary links between infectious disease microbiology, marine natural product chemistry and pharmacology. The first aim is to assess the antimicrobial properties of the marinopyrroles and napyradiomycins isolated from marine actinomycetes by measuring in vitro activity, capacity for resistance development, and synergistic activities with known antibiotics. The second aim is to determine the pharmacological characteristics of these novel classes of compounds by testing their in vitro bactericidal activity, post-antibiotic effect and cytotoxic effects. We will study the in vivo pharmacokinetic and pharmacodynamic profiles of the candidate antibiotics in a mouse model. The third aim is to define the mechanisms of action of the marinopyrrole and napyradiomycin classes of antibiotics by evaluating bacterial cell wall integrity and using radiolabeled precursors to measure changes in bacterial DNA, RNA and protein syntheses. We will collaborate with other laboratories to employ methods such as mass-spectrometry and structure-activity relationship studies to further understand mechanism of action. PUBLIC HEALTH RELEVANCE: The widespread emergence and increasing prevalence of infections caused by multiple drug-resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is a distinct medical concern. An urgent need exists for the discovery of novel antibiotics to treat these infections. The goal of this project is to discover and develop new antibiotics derived from marine- natural products to target drug-resistant MRSA and address this public health crisis.